To compare the protective effects of amifostine and dexrazoxane against the chronic toxicity induced by doxorubicin, spontaneously hypertensive rats (SHR)were treated with amifostine (200 mg/kg, i.p.), dexrazoxane (25 mg/kg, i.p.) or saline 30 min before the administration of doxorubicin (1 mg/kg, i.v.), once weekly for 12 weeks. Control animals received similar amounts of amifostine or saline. The SHR underwent necropsy examination one week after the last dosing, and cardiac, renal, and gastrointestinal lesions were graded semiquantitatively. Amifostine and dexrazoxane provided equal degrees of protection against the renal toxicity of doxorubicin. However, dexrazoxane was more cardioprotective than amifostine, and prevented the mortality induced by doxorubicin. This mortality was not decreased by pretreatment with amifostine. The loss of body weight caused by doxorubicin was actually worsened by coadministration of amifostine. These differences may be related to the fact that amifostine may act as a scavenger of reactive oxygen species, whereas dexrazoxane may prevent their formation.